<br>在黑色素瘤中靶向黑皮质素 1 受体：α-MSH-肽偶联物的生物活性,International Journal of Molecular Sciences

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在黑色素瘤中靶向黑皮质素 1 受体：α-MSH-肽偶联物的生物活性
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2024-01-16 , DOI: 10.3390/ijms25021095
Ildikó Szabó _{1,

2} , Beáta Biri-Kovács ₁ , Balázs Vári _{3,

4} , Ivan Ranđelović ₃ , Diána Vári-Mező _{1,

3,

4} , Éva Juhász ₅ , Gábor Halmos ₆ , Szilvia Bősze ₁ , József Tóvári _{3,

4} , Gábor Mező _{1,

7}

Affiliation

恶性黑色素瘤是最具侵袭性和耐药性的肿瘤类型之一，具有高转移特性。由于缺乏合适的化疗药物治疗药物，区域和远处转移的黑色素瘤患者的 5 年生存率低于 10%。提供几种有希望的结果的靶向肿瘤治疗可能是治疗恶性黑色素瘤的不错选择。我们的目标是开发用于靶向肿瘤治疗的新型黑色素瘤特异性肽-药物偶联物。黑皮质素-1 受体（MC1R）是一种负责黑色素生成的细胞表面受体，它在黑色素瘤细胞表面过表达，提供了一个很好的靶标。它的天然配体 α-MSH （α-黑素细胞刺激素）肽或其衍生物可能是用于此目的的潜在归巢装置。因此，我们制备了三种 α-MSH 衍生物-daunomycin （Dau）偶联物，并比较了它们的体外和体内抗肿瘤活性。Dau 具有自发荧光特性;因此，它适用于制备用于体外（例如细胞摄取）和体内实验的偶联物。Dau 通过不可切割的肟键连接到肽上，该键在我们之前的实验中被有效地应用，从而产生具有高肿瘤生长抑制活性的偶联物。结果表明，最有前途的偶联物是 Dau 与 Lys 侧链相连的化合物（Ac-SYSNleEHFRWGK（Dau=Aoa）PV-NH2）。使用该化合物证明黑色素瘤细胞的细胞摄取最高，在小鼠（B16 上为 38.6%）和人葡萄膜黑色素瘤（OMC-1 上为 55%）细胞上检测到最高的肿瘤生长抑制。该化合物的作用比游离药物的作用更明显。

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Targeting the Melanocortin 1 Receptor in Melanoma: Biological Activity of α-MSH–Peptide Conjugates

Malignant melanoma is one of the most aggressive and resistant tumor types, with high metastatic properties. Because of the lack of suitable chemotherapeutic agents for treatment, the 5-year survival rate of melanoma patients with regional and distant metastases is lower than 10%. Targeted tumor therapy that provides several promising results might be a good option for the treatment of malignant melanomas. Our goal was to develop novel melanoma-specific peptide–drug conjugates for targeted tumor therapy. Melanocortin-1-receptor (MC1R) is a cell surface receptor responsible for melanogenesis and it is overexpressed on the surface of melanoma cells, providing a good target. Its native ligand, α-MSH (α-melanocyte-stimulating hormone) peptide, or its derivatives, might be potential homing devices for this purpose. Therefore, we prepared three α-MSH derivative–daunomycin (Dau) conjugates and their in vitro and in vivo antitumor activities were compared. Dau has an autofluorescence property; therefore, it is suitable for preparing conjugates for in vitro (e.g., cellular uptake) and in vivo experiments. Dau was attached to the peptides via a non-cleavable oxime linkage that was applied efficiently in our previous experiments, resulting in conjugates with high tumor growth inhibition activity. The results indicated that the most promising conjugate was the compound in which Dau was connected to the side chain of Lys (Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2). The highest cellular uptake by melanoma cells was demonstrated using the compound, with the highest tumor growth inhibition detected both on mouse (38.6% on B16) and human uveal melanoma (55% on OMC-1) cells. The effect of the compound was more pronounced than that of the free drug.

更新日期：2024-01-18

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